The discriminative stimulus effects of several novel antidepressant drugs were studied in squirrel monkeys trained to discriminate methamphetamine (MA) from saline using conventional drug discrimination procedures. Substitution tests were completed initially with MA (0.03-1.0 mg/kg), prior to testing nomifensine (0.10-3.0 mg/kg), bupropion (0.30-3.0 mg/kg), trazadone (1-17.8 mg/kg), doxepin (0.30-5.6 mg/kg), fluoxetine (1-17.8 mg/kg), citalopram (1-17.8 mg/kg) and sertraline (1-10 mg/kg). For comparison purposes, a number of conventional tricyclic antidepressants (TCA's) were also studied in these monkeys. Fluoxetine, citalopram, sertraline and the TCA's, drugs which primarily inhibit NE or 5-HT uptake, failed to substitute for MA. Partial substitution (50-90% MA-lever responses) was obtained with nisoxetine, trazadone and doxepin, and full substition (>90% MA-lever responses) was observed with bupropion and nomifensine. These results suggest that antidepressants which function primarily as DA uptake inhibitors share discriminative stimulus properties with MA. However, the results with doxepin and trazadone suggest that other monoaminergic systems, particularly the NE system, may also be involved in mediating the MA-like effects of some clinically important antidepressants.